Loss of Peripheral Tolerance in Emphysema Phenotypes, Exacerbations, and Disease Progression
Loss of Peripheral Tolerance in Emphysema Phenotypes, Exacerbations, and Disease Progression
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DOI：
10.1513/annalsats.201503-115aw
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发表时间：
2015-11-01
影响因子：
8.3
通讯作者：
Kheradmand, Farrah
中科院分区：
文献类型：
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作者：
Bhavani, Sivasubramanium;Yuan, Xiaoyi;Kheradmand, Farrah
香烟引起的肺部疾病发生和发展的异质性强烈表明，有必要改善慢性阻塞性肺疾病和肺气肿患者的临床和表型特征。患有肺气肿的吸烟者加速肺功能丧失、心血管疾病发病率增加和肺癌发展的风险要高得多。人类转化研究和动物模型的最新证据表明，肺气肿与特异性抗原呈递细胞的激活有关，香烟烟雾可破坏肺部免疫耐受的诱导。定量评估自身反应性T淋巴细胞对人肺弹性蛋白片段表达的细胞因子显示辅助性T型1 （Th1）和Th17细胞的免疫应答与肺气肿之间存在很强的正相关。为了寻找能够降低自身免疫性炎症诱导阈值的因素，我们发现补体蛋白3 （C3）的切割产生生物活性分子（例如C3a）并激活肺抗原提呈细胞。在人类和临床前肺气肿模型中，C3a及其受体的自分泌和旁分泌功能在T细胞介导的香烟烟雾炎症反应中是必需的。靶向上游分子，减少自身反应性T细胞产生的潜力，可能会导致新的治疗方法的发展，以防止吸烟者肺气肿的进展。
Heterogeneity in the development and progression of cigarette smoke-induced lung diseases strongly argues for a need to improve the clinical and phenotypic characterization of patients with chronic obstructive lung disease and emphysema. Smokers with emphysema are at a much higher risk for accelerated loss of lung function, increased cardiovascular morbidity, and development of lung cancer. Recent evidence in human translational studies and animal models suggests that emphysema is associated with activation of specialized antigen-presenting cells and that cigarette smoke can disrupt the induction of immune tolerance in the lungs. Quantitative assessment of cytokines expressed by autoreactive T lymphocytes in response to human lung elastin fragments has shown a strong positive correlation between T helper Type 1 (Th1) and Th17 cells' immune responses and emphysema. In search of factors that could reduce the threshold for induction of autoimmune inflammation, we have discovered that cleavage of complement protein 3 (C3) generates bioactive molecules (e.g., C3a) and activates lung antigen-presenting cells. The autocrine and paracrine function of C3a and its receptor are required in T cell-mediated inflammatory responses to cigarette smoke in both human and preclinical models of emphysema. Targeting upstream molecules that reduce the potential for generation of autoreactive T cells could lead to the development of novel therapeutics to prevent progression of emphysema in smokers.